Unraveling immunological heterogeneity in recalcitrant AIH-PBC/PSC overlap syndromes: from molecular crosstalk to precision therapeutics.

The clinical management of autoimmune liver diseases is frequently complicated by the concomitant presentation of hepatitic and cholestatic features, an entity clinically designated as Overlap Syndrome. While the majority of patients respond to conventional combinatorial therapy involving corticosteroids and ursodeoxycholic acid, a significant subset exhibits a recalcitrant phenotype characterized by biochemical non-response and rapid fibrotic progression. The pathogenesis driving this therapeutic resistance remains incompletely defined, though emerging evidence implicates a distinct immunological architecture rather than a simple superposition of two diseases. This review delineates the multidimensional immunopathogenesis of AIH-PBC and AIH-PSC overlap syndromes with a specific focus on the interface between adaptive immunity and biliary epithelial senescence. We critically examine recent single-cell transcriptomic data that reveal specific pro-inflammatory macrophage niches and exhausted T-cell signatures unique to the overlap phenotype. Furthermore, we discuss the molecular crosstalk involving bile acid signaling and inflammatory cascades that perpetuates liver injury despite standard immunosuppression. Finally, we propose a paradigm shift towards precision medicine by evaluating the rationale for emerging biologic agents, including JAK inhibitors and B-cell depleting therapies, in the management of difficult-to-treat overlap syndromes.